Inbred SENCARA/Pt mice are susceptible to the induction of benign and malignant skin tumors, developing >0.6 carcinomas/mouse when treated by standard protocols. Crosses between SENCARA/Pt and resistant BALB/cAnPt mice revealed that multiple genes determine susceptibility. A genome scan led to the identification of a major locus controlling susceptibility on chromosome 5 in a 21 cM interval between D5Mit259 and D5Mit369. One candidate gene on chromosome 5 is the chemokine MGSA (or KC). Transgenic mice with the KC gene targeted to skin are 3-fold more susceptible to the induction of skin tumors than control mice. Possible modifier loci are indicated on chromosomes 9, 11 and 12. In a second cross, the F1 progeny of the cross between SENCARA/Pt and FVB/N mice (susceptible to progression) develop more papillomas than FVB/N mice, but the rate of conversion to malignancy was not increased compared to either parental strain.Marked synergism for tumor promotion between the phorbol ester 12-O-tetradecanoyphorbol-13-acetate (TPA)and agents that elevate intracelular calcium, such as thapsigargin or the calcium ionophore ionomycin, suggests a role for calcium in tumor promotion by phorbol esters. Synergism was seen only at suboptimal doses of TPA. K-ras mutations, which are rarely seen in mouse skin tumors, are frequent in rapidly-arising papillomas and carcinomas on the skin of mice initiated by N-methyl-N'-nitro-N-nitrosoguanidine and promoted by mezerein. H-ras mutations are found in skin tumors initiated by 7,12-dimethylbenz[a]anthracene and promoted by either TPA or mezerein.